Opoid dependency (OD) is associated with adverse clinical outcomes in hospitalized patients; nevertheless, the understanding of OD and its impact on cancer patients remains restricted. Alongside addressing the symptoms related to disease, hospitalized patients with OD also grapple with mental illness (MI) challenges and the risk of infectious consequences (ICs), which remain unrecognized in cancer patients. We utilized national inpatient database to examine patient and clinical characteristics among renal cell carcinomas (RCC), prostate cancers (PC) and cancers of the lip, oral cavity, and pharynx (CLOP). We used generalized linear models to evaluate the association of OD and outcome of burden of illness (BOI), specifically length of stay (LOS). We also evaluated the association between OD and emergency department (ED) referral/admission status, ICs (specifically septicemias), weight loss, fluid and electrolyte disorders (FED), status of MI screening, and anxiety and depressive disorders. Of the 88,105 RCC there were 610 OD patients; PC (209,410) with 1115 OD; CLOP (54,265) with 495 OD. PC patients with OD were associated with longer LOS (Coefficient, 1.59; 95
Cancer is increasingly recognized as a systemic disease whose biology is shaped by reciprocal interactions with its microenvironment, including the central and peripheral nervous systems. Recent evidence demonstrates that neural inputs can directly promote tumour growth through synaptic, paracrine, and neuroendocrine mechanisms, and that these inputs intersect with canonical drug-resistance pathways, creating new opportunities and challenges for precision oncology. Primary brain tumours such as gliomas form bona fide functional synapses with neurons, hijacking both excitatory (AMPA/NMDA) and inhibitory (GABA_A) inputs to sustain proliferation. Comparable mechanisms are now described in brain metastases and, remarkably, in small cell lung cancer (SCLC), where cortical and vagal neurons establish synaptic contacts with tumour cells. Beyond synaptic communication, paracrine neurotransmitter signalling, tumour innervation, autonomic balance (β-adrenergic versus vagal tone), and systemic stress responses jointly modulate tumour biology, immune surveillance, and therapeutic response. Convergent evidence further indicates that neural and stress-related signalling cooperates with classical resistance circuits—including p53–EGFR–ERK signalling, P-glycoprotein–mediated drug efflux, reactive oxygen species (ROS)–dependent redox programmes, and adipokine–Hsp90 axes—to attenuate the efficacy of chemotherapy, targeted agents, and immune checkpoint inhibitors. Neuron–tumour interactions represent a novel and clinically actionable dimension of cancer pathogenesis that extends well beyond gliomas. Targeting neuron–tumour synapses, neurotransmitter pathways, autonomic inputs, and the resistance circuits with which they intersect offers new therapeutic opportunities, but translation requires careful attention to specificity, neurological safety, and rational combination with cytotoxic, targeted, and immune therapies. Cancer is not driven solely by genetic mutations; it is also shaped by signals from the nervous system. This review synthesizes how nerves and brain activity directly influence tumour growth across multiple diseases—including gliomas, small cell lung cancer, breast cancer, pancreatic cancer, and prostate cancer—and how these neural signals converge with metabolic and drug-resistance pathways that limit the efficacy of conventional therapy. Recent discoveries show that some cancers form direct synapse-like connections with neurons and exploit neurotransmitters to fuel tumour progression and treatment escape. Understanding these interactions opens new therapeutic opportunities—such as targeting neural signalling, autonomic pathways, or neuro-modulated resistance mechanisms—and positions the nervous system as a previously underappreciated but clinically relevant driver of cancer behaviour.
Synthetic cobalt Schiff bases have recently emerged as promising metal-based anticancer candidates. In this study, we investigated the biological effects of a mononuclear octahedral cobalt(III) Schiff base complex [CoL3] (L = 2-((allylimino) methyl) − 6-methoxyphenol)) on the cell cycle progression and apoptosis of the HT-29 cells, a human colorectal cancer cell line. Cytotoxic activity of [CoL3] was evaluated using the MTT assay. Then, its impact on apoptosis was assessed via annexin V-FITC/propidium iodide (PI) staining. To elucidate the underlying mechanisms, we employed flow cytometry, real-time PCR, and Western blotting to analyze cell cycle distribution and the expression of apoptotic and cell cycle-related genes. Our results revealed that [CoL3] exhibited potent cytotoxicity with an IC50 of 3.47 µM and induced cell cycle arrest in the G1/S and G2/M transition phases in colorectal cancer cells (p < 0.001, p < 0.01). Treatment of colorectal cancer cells with [CoL3] resulted in a significant decrease in CDK4 and CDK6 expression, with mean values of 0.62 (p < 0.05) and 0.33 (p < 0.01), respectively. Additionally, the protein expression of CDK4 and CDK6 was downregulated, with mean protein intensities of 0.48 and 0.79, respectively (p < 0.001), supporting its role in G1 phase blockade. Moreover, [CoL3] downregulated BCL2 (p < 0.01), which was associated with increased early and late apoptosis in treated cells. Docking analyses further demonstrated favorable spontaneous binding of [CoL3] to CDK4 and CDK6, reinforcing its mechanistic involvement in cell cycle inhibition. Collectively, these findings indicate that [CoL3] induces cell-cycle arrest and promotes apoptosis in HT-29 colorectal cancer cells, potentially through the downregulation of CDK4/6 and BCL2.
In lung adenocarcinoma (LUAD), DNA methylation-mediated gene silencing may contribute to tumor initiation, progression, and heterogeneity in treatment response. However, the key methyltransferases involved and their therapeutic potential have not been systematically characterized. This study aimed to address three major questions: which methylation-associated gene silencing events occur in LUAD, which upstream methyltransferase predominantly drives these events, and whether targeted inhibition of this enzyme can mitigate drug-resistant phenotypes and enhance chemosensitivity. Differential expression analysis was initially performed using the GSE75037 dataset to screen candidate genes. Expression quantitative trait locus (eQTL) and protein quantitative trait locus (pQTL) data were then integrated, and key candidate genes were prioritized according to the concordance in the directions of genetic effects. Subsequently, mediation Mendelian randomization analysis was conducted to determine whether the effect of locus-specific methylation on LUAD was mediated by QDPR expression, thereby providing genetic causal evidence that methylation contributes to transcriptional repression. In addition, the associations between DNA methylation-related enzymes and QDPR expression were analyzed in the GSE33532, GSE43458, and GSE75037 datasets, followed by cross-dataset validation to identify potential key upstream regulators. Finally, cell-based experiments were performed to verify the functional effects of DNMT1 inhibition. Changes in QDPR expression were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting, and the potential chemosensitizing effect of DNMT1 inhibition in combination with platinum-based chemotherapy was further evaluated in patient-derived organoids. This study provided genetic causal evidence that locus-specific methylation influences LUAD risk, with part of this effect mediated by QDPR expression. Analyses across multiple independent datasets consistently suggested that DNMT1 may act as a key upstream epigenetic regulator contributing to the reduced expression of QDPR. Functional experiments demonstrated that DNMT1 inhibition increased QDPR expression and suppressed the proliferation and migration of LUAD cells. Drug sensitivity assays using patient-derived organoids further showed that DNMT1 inhibition exerted a significant chemosensitizing effect in the platinum low-sensitivity group. This study suggests that DNMT1 may contribute to the reduced expression of QDPR and related malignant phenotypes through epigenetic regulation. Functional and drug sensitivity experiments further support the potential of DNMT1 as a therapeutic target for improving the response to platinum-based chemotherapy in a subset of patients with LUAD. These findings provide a potential therapeutic target and offer mechanistic insights into treatment response heterogeneity and chemoresistance in LUAD.
Gastrointestinal (GI) cancers encompass malignant conditions of the GI tract and accessory digestive organs, including the esophagus, gastric cancer (GC), biliary system, hepatocellular carcinoma (HCC), pancreatic cancer (PC), and colorectal cancer (CRC). Globally, CRC ranks as the third most commonly diagnosed cancer, with gastric, hepatic, and esophageal cancers following in fifth, sixth, and seventh places, respectively. PC contributes notably to cancer mortality, ranking 12th in incidence and 7th in mortality. Despite major advances in diagnosis and treatment, GI cancers remain among the most aggressive malignancies and continue to drive substantial global morbidity and mortality. In 2020, GI cancers accounted for more than 4.8 million new cases and 3.4 million deaths. Although early-stage GI tumors can be surgically resected with curative intent, the overall 5-year relapse rate remains high. Neoadjuvant or adjuvant chemotherapy and radiotherapy provide only modest long-term survival improvements when applicable. In recent decades, prognosis for advanced GI cancers has improved due to tailored therapies that combine cytotoxic and targeted agents and integrate systemic treatments with more effective surgical and locoregional approaches. Nevertheless, GI malignancies remain a leading cause of cancer death, underscoring the need for novel therapeutic options. A central molecular driver is the PI3K/AKT/mTOR signaling axis, which governs chemotherapy resistance, metastasis, survival, metabolism, and growth, and modulates the tumor microenvironment via angiogenesis and inflammatory infiltration. Dysregulation of this axis is common across GI cancers, guiding exploration of pathway-targeted therapies, alone or in combination. Although several agents show promise, toxicities such as neuropsychiatric effects, diarrhea, hepatotoxicity, and hyperglycemia limit clinical utility. Therefore, refined personalization and combination strategies targeting PI3K/AKT/mTOR are critical to improving efficacy and reducing resistance in GI malignancies. Aberrant PI3K/AKT/mTOR signaling drives progression, metastasis, and therapy resistance in gastrointestinal cancers. Preclinical studies show PI3K/AKT/mTOR inhibitors reduce growth, induce cell death, and boost chemosensitivity in GI cancers. Clinical use of pathway inhibitors is limited by toxicity and lack of molecular stratification, emphasizing the need for biomarker-driven combination therapies.
Persistent infection with high-risk human papillomavirus type 16 (HPV16) is a major cause of cervical cancer and is associated with viral oncoproteins that disrupt tumor suppressor pathways and influence cellular microRNA (miRNA) expression. Given increasing interest in phytochemicals as potential anticancer agents, this study evaluated the effects of chrysin, a natural flavonoid, on cell viability, selected cancer-related miRNAs, and HPV16 E6 protein levels in HPV16-positive CaSki cervical cancer cells. CaSki cells and normal human dermal fibroblasts (HDF) were treated with chrysin (31.5–500 µg/ml) for 24 and 48 h. Cell viability was assessed by MTT assay. Expression of miR-34a, miR-218, miR-20a, miR-195, and miR-23b was quantified by qRT-PCR (2−ΔΔCt method), and E6 protein levels were analyzed by Western blot. Chrysin selectively reduced CaSki cell viability with minimal toxicity toward HDF cells, resulting in a high selectivity index. Treatment was associated with increased expression of miR-34a (10.05-fold, P < 0.0001) and miR-218 (5.64-fold, P < 0.01), a moderate increase in miR-20a (1.7-fold, P < 0.05), decreased miR-195 expression (0.18-fold, P < 0.01), and no significant change in miR-23b. A significant reduction in E6 protein levels was also observed (0.64 ± 0.01 vs. control, P < 0.001). These findings indicate that chrysin treatment is associated with selective cytotoxicity and concurrent modulation of HPV16 E6 protein levels and several cancer-related miRNAs in CaSki cells. Further studies in additional cellular models and mechanistic systems are required to clarify the underlying pathways.
Kynureninase (KYNU), a hydrolase in tryptophan metabolism, has been implicated in cancer progression. However, the therapeutic relevance of targeting KYNU-mediated inflammatory signaling in triple-negative breast cancer (TNBC) remains poorly defined High-throughput virtual screening (HTVS) of the ChemBridge library, combined with protein–ligand interaction profiling, molecular dynamics simulations (GROMACS), and binding free energy analysis (GMX_MMPBSA), was employed to identify KYNU inhibitors. In vitro assays were performed in SUM159, MDA-MB-231, and HBL-100 cell lines. KS79356 was identified as the lead compound, displaying strong binding affinity (− 7.8 kcal/mol), stable interactions (RMSD ≈ 0.075 nm), and favorable binding free energy (ΔG = − 23.93 kcal/mol). KS79356 effectively inhibited KYNU activity (IC₅₀ = 63.7 nM) and selectively suppressed proliferation of SUM159 (GI₅₀ = 233 nM) and MDA-MB-231 (GI₅₀ = 450.8 nM) cells. Mechanistically, KS79356 downregulated TNF-α–induced activation of the NFκB–CD44–Akt signaling axis, leading to reduced proliferation, invasion, and trans-endothelial migration, while inducing both early and late apoptosis in TNBC cells. By targeting KYNU and attenuating the TNF-α/NFκB/CD44–Akt signaling axis, KS79356 demonstrates strong antitumor activity in TNBC. These findings highlight the novelty of KYNU as a therapeutic target and support the development of KS79356 as a potential treatment strategy for TNBC progression and metastasis. Clinical trial registration Not applicable. Graphical abstract showing KS79356 as a KYNU inhibitor identified via virtual screening and molecular dynamics, validated in TNBC cells. KS79356 suppressed TNF-α/NFκB–CD44–Akt signaling, reducing proliferation, migration, and trans-endothelial migration, while promoting apoptosis The analysis of KYNU's crystal structure identified key active site residues involved in ligand binding, complemented by an ΑFold-predicted full-length structure for comprehensive insights. Through diversity-based high-throughput virtual screening of the ChemBridge library, KS79356 was identified as a lead compound, exhibiting low docking energy values and favorable ADMET properties for targeting KYNU. Molecular dynamics simulations demonstrated KS79356 to retain a stable binding position within the KYNU active site. KS79356 effectively inhibited KYNU activity and showed antiproliferative effects in TNBC cell lines. KS79356 downregulated TNF-α-stimulated p-NF-κB, CD44, and p-Akt signaling in TNBCs while inhibiting migration and enhancing apoptosis in these cells.
Neuroblastoma is a highly aggressive childhood malignancy originating from neural crest-derived cells. Narciclasine, an Amaryllidaceae-derived alkaloid isolated from plants such as Lycoris radiata, has been reported to exhibit various pharmacological activities; however, its effects in neuroblastoma remain poorly understood. In this study, we investigated the effects of narciclasine on SH-SY5Y neuroblastoma cells, focusing on proliferation, migration, apoptosis, DNA damage, and FAK/PI3K-associated signaling. Cell viability was evaluated using the CCK-8 assay; proliferation by Ki67 immunofluorescence staining; migration and colony formation by wound-healing and colony formation assays; apoptosis by TUNEL and cleaved caspase-3 immunofluorescence staining; DNA damage by COMET assay; and FAK/PI3K-related protein expression by immunohistochemistry and Western blot analysis. Treatment with 50 and 100 nM narciclasine significantly reduced SH-SY5Y cell viability while exhibiting comparatively lower cytotoxic effects in HUVEC cells under the tested conditions; therefore, these concentrations were selected for subsequent experiments. Narciclasine treatment also reduced cell proliferation, migration, and colony formation, while increasing apoptosis and DNA damage. Immunofluorescence analyses demonstrated decreased Ki67 expression and increased cleaved caspase-3 immunoreactivity in narciclasine-treated groups. In addition, immunohistochemical and Western blot analyses revealed reduced expression levels of FAK and PI3K following narciclasine treatment. Collectively, these findings suggest that narciclasine exerts anti-neuroblastoma effects associated with reduced proliferative and migratory activity, increased apoptotic response, and modulation of FAK/PI3K-associated signaling in SH-SY5Y cells. Further studies are needed to clarify the precise molecular basis and therapeutic relevance of these effects.
Advanced EGFR-mutant non-small cell lung cancer (NSCLC), specifically tumors harboring classical activating mutations (exon 19 deletions and L858R substitutions, which are the exclusive focus of this review), is no longer a single-treatment landscape. The MARIPOSA and FLAURA2 phase 3 trials have established that combination regimens of amivantamab plus lazertinib and osimertinib plus platinum-pemetrexed, respectively, extend both progression-free and overall survival compared with osimertinib monotherapy. Each carries substantially greater toxicity, treatment complexity, and cost. No validated, prospective framework exists to guide first-line selection between combination and single-agent strategies. Decision-making is currently anchored to trial eligibility criteria and institutional norms rather than individualized risk stratification. This review synthesizes evidence from landmark trials, molecular biomarker analyses, and real-world cohort studies to propose a practical risk-adapted algorithm integrating tumor biology, molecular co-alterations, patient performance status, comorbidities, logistical feasibility, and treatment preference. Patients with biologically high-risk features, including liver metastases, baseline central nervous system (CNS) involvement, circulating tumor DNA (ctDNA) elevation, or heavy disease burden, may derive the greatest absolute benefit from combination therapy. TP53 co-mutation warrants consideration but should be interpreted as a prognostic marker rather than a definitive treatment-selection criterion given conflicting predictive data across trials. The subcutaneous (SC) formulation of amivantamab, demonstrated in PALOMA-3 to reduce infusion-related reactions and administration time relative to the intravenous formulation, may improve the tolerability and logistical feasibility of MARIPOSA-based therapy, though prospective comparative evidence across formulations remains limited. Prospective biomarker-driven trials are needed to validate treatment selection; until that evidence matures, individualized shared decision-making guided by the proposed algorithm is the most defensible clinical approach.
Arginine vasopressin hormone (AVP) is ectopically expressed in breast cancer. Also, in intestinal epithelial and mesangial cells, for example, it acts as a growth-promoting factor when it binds to the GPCR receptor and triggers multiple downstream mitogenic signalling pathways leading to cell proliferation. As Dynamin 2 GTPase (Dyn2) is an integral protein involved in membrane receptor endocytosis, it is unclear how far AVP and Dynasore (DYN), a selective Dyn2 GTPase inhibitor, can modulate the proliferation of invasive breast cancer cells. To explore this, triple-negative breast cancer cells (MDA MB-231), which express V1A, were exposed to 100 nM AVP for 24 h, either alone or in combination with DYN. The cytotoxic effect, apoptosis, and autophagy-mediated cell death were assessed and compared to untreated cells and cells in which the PI3K/AKT pathway was inhibited by wortmannin (Wort). Also, cell cycle progression, migration, and the expression of the drug-resistance gene were investigated. We found that AVP alone developed apoptosis in about 20
Brain metastasis remains one of the most devastating complications of lung cancer, contributing to poor prognosis and limited therapeutic efficacy. Increasing evidence suggests that the development and progression of lung cancer brain metastasis are shaped by dynamic and reciprocal interactions among tumor cells, neural components, and immune elements within the brain microenvironment. Neurotrophic factors, neurotransmitters, and glial cells participate in blood–brain barrier remodeling, immune modulation, and metabolic adaptation, while tumor cells exploit these neuro–immune interactions to facilitate colonization, survival, and therapeutic resistance. In this review, we organize current knowledge within a stage-specific and spatiotemporal framework encompassing early blood–brain barrier disruption and colonization, intermediate microenvironmental remodeling with immunosuppression formation, and late-stage stabilization characterized by sustained neuro–tumor interaction. Importantly, rather than summarizing neural or immune pathways in isolation, we integrate adaptive immune dynamics, glial reprogramming, and neurotransmitter-dependent signaling into a unified neuro–immune–tumor network model and explicitly prioritize context-dependent hub molecules according to graded levels of supporting evidence. Within this staged framework, we delineate regulatory axes that may define context-dependent therapeutic windows. Rather than providing an exhaustive catalog of mechanisms, we emphasize pathways with emerging translational relevance, including BDNF–TrkB signaling, adrenergic pathways, and glial reprogramming. This integrative perspective aims to clarify the organizational principles of neuro–immune–tumor networks in lung cancer brain metastasis and to inform future studies exploring combinatorial neural and immune modulation strategies, biomarker development, and rational clinical trial design, while acknowledging that direct LCBM validation remains limited for some pathways.
Leptin, an adipokine primarily secreted by adipose tissue, has been implicated in tumor progression by regulating angiogenesis. Leptin also plays a key role in tumor vascularization by promoting vasculogenic mimicry (VM). During tumor progression, leptin activates several signaling pathways, including the focal adhesion kinase (FAK) pathway. This study aimed to determine whether leptin promotes and regulates angiogenesis and VM through the FAK pathway. We used the chick chorioallantoic membrane (CAM) as a model to evaluate blood vessel formation and to induce tumors to assess angiogenic expression. Matrigel-based cell cultures were used to analyze the formation of tubular structures characteristic of VM. The expression of specific markers was then evaluated for each process. These models were employed with or without the inhibitor PF-573,228. Our results showed that leptin enhances the sprouting, branching, and vasodilation of blood vessels via FAK signaling by increasing the expression of vascular endothelial growth factor (VEGF) and N-cadherin in tumors derived from MCF-7 and MDA-MB-231 cells. Furthermore, leptin stimulation promoted tubular-type VM in MCF-7 cells and matrix-type VM in MDA-MB-231 cells; the former was dependent on FAK signaling. Lastly, leptin increased the levels of several proteins associated with angiogenesis and VM, including TIE-1, MMP-9, VE-cadherin, ANG-2, VEGF, and VEGFR1. In conclusion, leptin promotes tumor vascularization in breast cancer through angiogenesis and VM, in a manner dependent on FAK signaling
Background: Although cytarabine remains a cornerstone chemotherapeutic agent for Acute lymphoblastic leukemia (ALL), its clinical efficacy is frequently compromised by systemic toxicity and resistance mechanisms, notably telomerase activation via hTERT upregulation. This study investigates the synergistic potential of Zataria multiflora extract (ZME) combined with cytarabine to induce apoptosis in pre-B ALL cells (NALM-6) and explores the underlying molecular mechanisms. Methods: In vitro experiments were conducted using the NALM-6 cell line. Cell viability was assessed via Trypan blue exclusion and MTT assays. Apoptosis was quantified using Annexin V/PI flow cytometry. The mRNA expression levels of BAX, BCL2, and hTERT were evaluated by qRT-PCR. Additionally, in silico molecular docking was performed to analyze the interactions between the primary active components of ZME (thymol and carvacrol), cytarabine, and the MDM2 protein. Results: Single-agent treatments (100 µg/mL ZME or 0.5 µM cytarabine) yielded 70–80
Doxorubicin (Dox) remains a cornerstone chemotherapeutic for hepatocellular carcinoma (HCC), yet its efficacy is constrained by systemic toxicity and intrinsic chemoresistance. Nanocarrier systems are proposed to overcome these limitations. This study aimed to develop and evaluate a chitosan-silver nanoparticle (Cs-AgNPs) system as a Dox delivery vehicle in HepG2 cells. Cs-AgNPs+Dox nanoparticles were synthesized and characterized by FTIR, XRD, and SEM. Drug-loading efficiency, release kinetics, and cytotoxicity were assessed and compared with those of free Dox. The modulation of PI3K/AKT/mTOR, NF-κB, autophagy, and apoptosis pathways was investigated using RT-qPCR and Western blotting. The formulation produced spherical, stable nanoparticles with high encapsulation efficiency and sustained release. Unexpectedly, at sub-toxic concentrations (6.25-50 µg/mL), Cs-AgNPs+Dox exhibited significantly lower cytotoxicity than free Dox. Mechanistic studies revealed strong activation of the PI3K/AKT/mTOR and NF-κB signaling cascades, accompanied by upregulation of autophagy markers (LC3, Beclin1) and reduced Caspase-3 expression. These findings indicate that the nanocarrier itself induces a pro-survival, chemoresistant phenotype in HepG2 cells. Cs-AgNPs is not an inert carrier but an active biological modulator that can antagonize Dox-induced cytotoxicity by stimulating key survival and autophagy pathways. This work underscores the importance of assessing the intrinsic bioactivity of metallic polymer hybrid nanocarriers, as their inadvertent compromise of therapeutic efficacy is a concern. Future optimization should integrate pathway-specific inhibitors to mitigate nanocarrier-induced resistance.
Oral carcinoma is the sixth most prevalent cancer type with a poor 5-year survival rate. mRNA-lipid nanoparticle-based immunotherapy can overcome the challenges associated with conventional treatment options. Here, we investigated the immunogenicity and antitumor efficacy of survivin antigen encoded mRNA lipid nanoparticles (LNPs) in combination with anti-CTLA-4 immune checkpoint inhibitor. Survivin mRNA was synthesized by in vitro transcription technique after cloning the antigenic target sequence into an expression vector. The mRNA-LNPs were prepared with lipids, ALC-0315, DOPE, and cholesterol using a droplet-based microfluidic device. The average particle size, polydispersity index and encapsulation efficiency of mRNA-LNPs was found to be 305 ± 68 nm, 0.11, and 65 ± 3.9
Lipid Peroxidation (LPO) is a process driven by oxidative stress that is notoriously implicated for triggering various diseases. In cancer, however, LPO acts as a double-edged sword, fueling tumor growth while showing promise as a treatment target. This review performs a deep dive into this duality and highlights its twofold involvement across various malignancies, including colorectal, breast, and lung cancers. LPO is closely linked with oxidative stress, which contributes to DNA damage, chronic inflammation, and other processes that cause cancer initiation. Other LPO-derived mechanisms, such as the production of destructive reactive aldehydes, NF-κB activation, and immune evasion, are also examined, showing LPO's ability to fuel tumor growth and expansion. In contrast, LPO's destructive power can be redirected to target cancer cells by inhibiting key antioxidant enzymes or silencing Nrf2. Although further research is critically needed to refine these approaches, they represent promising new avenues for treating cancers that resist conventional therapies and may help guide future precision oncology strategies.
Cancer-associated venous thromboembolism (VTE) is a common and life-threatening complication in patients with colorectal cancer (CRC) following surgery. This study aims to develop and validate a nomogram for accurately predicting the risk of VTE in CRC patients undergoing postoperative chemotherapy. This study included a total of 1,397 CRC patients who received postoperative chemotherapy at Chongqing University Cancer Hospital. The patients were randomly divided into training cohort and validation cohort in a 7:3 ratio. LASSO regression and multiple logistic regression were employed to identify independent risk factors for VTE and construct a nomogram. The model performance was evaluated using receiver operating characteristic (ROC) curves, area under the curve (AUC), calibration curves and decision curve analysis (DCA). Among the patients, 116 cases (8.30
Total neoadjuvant therapy (TNT) has emerged as a key treatment paradigm for locally advanced rectal cancer, reducing distant metastasis rates and facilitating organ preservation in selected patients. However, treatment response remains heterogeneous, highlighting the need for biomarkers that can guide treatment selection and optimise outcomes. This narrative review synthesises the current evidence regarding tumour-intrinsic genomic biomarkers associated with response to neoadjuvant therapy, encompassing somatic mutations, germline polymorphisms, gene expression profiles, mismatch repair (MMR) status, protein expression, epigenetic markers, and circulating tumour-derived biomarkers across conventional chemoradiotherapy (CRT) and TNT paradigms. Across the reviewed literature, individual somatic mutations, including KRAS, TP53, and BRAF, demonstrated limited reproducibility as predictive biomarkers, although KRAS mutations were recurrently associated with lower pathological complete response (pCR) rates in CRT-era cohorts. Germline polymorphisms in DNA repair (XRCC1) and folate metabolism (MTHFR) genes showed inconsistent associations with treatment response. In contrast, transcriptomic biomarkers demonstrated greater biological coherence, with proliferative, epithelial–mesenchymal transition, and metabolic signatures frequently associated with treatment resistance, while multi-gene classifiers generally outperformed single-gene markers. Among currently available tumour-intrinsic biomarkers, MMR deficiency was the most consistently reported biomarker associated with reduced response to fluoropyrimidine-based regimens, including TNT, although TNT-specific evidence remains comparatively limited. Dynamic circulating tumour DNA (ctDNA) monitoring, particularly ctDNA clearance during or after therapy, was consistently associated with pathological response and long-term oncologic outcomes across reviewed studies, whereas baseline ctDNA levels showed limited predictive value. Overall, the reviewed literature suggests that biomarker research in rectal cancer has evolved from single-gene analyses towards pathway-level and dynamic biomarkers. The integration of transcriptomic signatures, MMR status, and dynamic ctDNA monitoring may represent a promising strategy for personalising neoadjuvant therapy, improving patient selection for organ-preserving approaches, and enhancing oncologic outcomes in locally advanced rectal cancer. Nevertheless, the evidence base remains heterogeneous, and further prospective validation, assay standardisation, and evaluation within contemporary TNT cohorts are required before these biomarkers can be routinely incorporated into clinical decision-making.
Accumulating evidence from studies in other tumour types suggests that mesenchymal stromal cells (MSCs) may influence macrophage polarization, but the underlying mechanisms in renal cell carcinoma (RCC) remain unclear. In this study, renal carcinoma-derived MSCs (RCC-MSCs) were isolated from the tumour tissue of a patient with clear cell renal cell carcinoma, and BM-MSC-derived MSC1 was included as an exploratory reversal model rather than as a biologically matched comparator. THP-1-derived macrophage models, together with co-culture assays, flow cytometry, Western blotting, quantitative real-time PCR, and ELISA, were used to evaluate macrophage phenotypes and cytokine secretion. Patient-derived RCC-MSCs from a single ccRCC specimen promoted M2-like macrophage polarization in vitro, and this effect was attenuated by NF-κB inhibition with pyrrolidine dithiocarbamate (PDTC). In turn, RCC-MSC-primed macrophages enhanced the growth, migration, and invasion of 786-O cells in vitro, whereas blockade of NF-κB attenuated these tumour-promoting effects. In an exploratory in vitro setting, BM-MSC-derived MSC1 favoured partial reprogramming of M2 macrophages toward an M1-like phenotype. Collectively, these findings suggest that patient-derived RCC-MSCs from a single ccRCC specimen may promote M2-like macrophage polarization through NF-κB-related signalling and enhance malignant phenotypes of 786-O cells in vitro, while BM-MSC-derived MSC1 supports the plasticity of macrophage polarization in an exploratory setting.
Hepatocellular carcinoma (HCC) has an extremely poor prognosis. The emergence of immune checkpoint inhibitors (ICIs) has fundamentally transformed the therapeutic landscape for HCC. However, due to the limited response rate and complex resistance mechanisms of monotherapy, the core of clinical practice has shifted towards ICI-based combination strategies. This article systematically reviews the biological basis—primarily the immune microenvironment—and clinical evidence, including the limitations of monotherapy and the optimization of combination regimens, underlying this paradigm shift, as well as the challenges in achieving precision medicine (such as efficacy prediction and resistance). Finally, it points out that future breakthroughs rely on the integrated application of multi-omics-guided personalized regimens, engineered immune cell technologies, and AI-based predictive models. In summary, advancing HCC immunotherapy from broad combination strategies toward individualized precision combinations represents a promising direction for addressing current limitations and improving therapeutic benefit.
